US3983124A - Fluorene compounds - Google Patents

Fluorene compounds Download PDF

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US3983124A
US3983124A US05/317,238 US31723872A US3983124A US 3983124 A US3983124 A US 3983124A US 31723872 A US31723872 A US 31723872A US 3983124 A US3983124 A US 3983124A
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bis
fluorene
fluoren
basic
compounds
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William L. Albrecht
Stephen W. Horgan
Arthur D. Sill
Robert W. Fleming
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Richardson Vicks Inc
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Richardson Merrell Inc
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Priority to ZA738206A priority patent/ZA738206B/xx
Priority to AU61880/73A priority patent/AU478050B2/en
Priority to CA184,556A priority patent/CA1017333A/en
Priority to IL43675A priority patent/IL43675A/en
Priority to DE2362663A priority patent/DE2362663A1/de
Priority to GB5829073A priority patent/GB1417267A/en
Priority to FR7345519A priority patent/FR2211243B1/fr
Priority to JP48141919A priority patent/JPS4988849A/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • This invention relates to new organic chemical compounds, to their methods of preparation, and to pharmaceutical compositions which contain these compounds as the active ingredient.
  • the compounds described herein are useful antiviral agents which inhibit or inactivate viruses by their administration to either infected or non-infected hosts.
  • viruses play a vital role in a broad range of diseases, some of which represent the most serious of man's ills.
  • Arthritis, juvenile arthritis, diabetes, Hodgkin's disease, and various immunological diseases and degenerative diseases of the central nervous system have been linked with viruses as the causative agent.
  • virus infections is primarily achieved by means of immunization vaccines.
  • immunization vaccines For example, poliomyelitis, smallpox, measles and influenza are well recognized diseases in which viral vaccines have proven effective.
  • viral vaccines have had only a moderate success in animal prophylaxis.
  • Each vaccine acts primarily against a specific virus and is not heterophilic in the protection it offers.
  • vaccines have not provided a practical solution against the wide array of infectious viruses, even where limited, as for example, to respiratory viruses alone.
  • This invention relates to new derivatives of fluorene, to their methods of preparation, compositions thereof and to their usefulness as pharmaceutical agents. More particularly, the compounds of the present invention are 2,7-bis-basic-fluorenes, 2,7-bis-basic-fluoren-9-ols and 2,7-bis-basic fluoren-9-ones, which are useful as anti-viral agents. Still more particularly, the compounds of the present invention are represented by the following structural formula: ##SPC1##
  • A is selected from the group consisting of CH 2 , ##STR1## and a sigma bond
  • n is an integer of from 1 to 4
  • R and R 1 are each selected from the group consisting of hydrogen, lower alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms, alkenyl having from 3 to 6 carbon atoms in which the unsaturation is in a position other than the 1-position of the alkenyl group, and when R and R 1 are taken together with the nitrogen atom to which they are attached, they represent the pyrrolidinyl, piperidino or the morpholino radical;
  • Z is selected from the group consisting of H 2 , O and H(OH) with the proviso that when Z is H(OH), the symbol A can only represent CH 2 , ##STR2## or a sigma bond; and their pharmaceutically acceptable acid addition salts.
  • the compounds within the scope of the present invention as represented by the above general formula include both the free base form as well as pharmaceutically acceptable acid addition salts thereof.
  • such salts are crystalline materials which are soluble in water and various hydrophilic organic solvents, and which, in comparison to their free base forms, generally demonstrate higher melting points and exhibit an increased stability.
  • the bis-basic fluorene derivatives of the present invention are prepared by the oxidation and/or reduction of the corresponding bis-basic ketones of fluorene (II), which are fully described in copending application, Ser. No. 23,468, filed Mar. 27, 1970, and whose counterpart has been published as Belgium Patent No. 764,870.
  • the preparation of the various classes of compounds described and claimed herein can be schematically represented as follows: ##SPC2##
  • R and R 1 have the values previously assigned and p is an integer of from 1-5.
  • the 2,7-bis-basic fluoren-9-ones (I), wherein Z is oxygen, are prepared by the oxidation of the corresponding 2,7-bis-basic fluorenes or 2,7-bis-basic fluoren-9-ols, wherein Z is hydrogen and H(OH), respectively, in accordance with the procedure of Y. Sbluak, J. Am. Chem. Soc. 80, 5449 (1958).
  • the oxidation to the fluoren-9-ones is highly selective and is readily accomplished by bubbling oxygen through a pyridine solution containing the fluorene or fluorenol derivative in the presence of a catalytic quantity of benzyltrimethylammonium hydroxide.
  • the fluoren-9-ol derivatives are obtained by a reduction of the corresponding fluoren-9-one derivatives. In general, either one of two methods can be employed depending upon the length of the particular side chain desired.
  • the 2,7-bis-basic methyl fluoren-9-ols i.e., (I) wherein Z is H(OH), A is a sigma bond and n is equal to 1, are prepared by a lithium aluminum hydride reduction of the corresponding 2,7-bis-carboxamides of fluoren-9-one as illustrated in the following reaction scheme: ##SPC3##
  • the symbols n, R and R 1 have the values previously assigned, whereas the symbol A has the proviso limitation earlier mentioned.
  • those fluoren-9-ones already containing a ketone or oxime in their side chain will not survive further reduction, and other methods, not included in the present invention, must be employed for their preparation.
  • the compounds of this invention are preferably administered to a suitable host using a variety of compositions.
  • Such compositions may be administered either prior to infection, as a prophylactic use or treatment, or they may be therapeutically administered subsequent to infection, as a curative use or treatment.
  • the compounds of this invention may also be applied externally or topically directly at the situs of infection, or they may be administered internally or systemically irrespective of whether the treatment is prophylactic or curative in nature. In either event, replication of the infectious virus is inhibited or prevented with the concomitant result that the various disease symptoms characteristic of the pathogenic virus infection are no longer present.
  • the compounds of the present invention include basic side chains in the 2 and 7-positions of a fluorene, fluoren-9-ol and fluoren-9-one nucleus.
  • These basic side chains can be regarded as consisting essentially of a bridging function connected directly to the aromatic nucleus, a basic amino group, ##STR3## at the terminal end of said basic side chain, and an alkylene chain, --(CH 2 ) n -- separating the bridging function from the basic amino group.
  • the basic amino group is a primary, secondary or tertiary amino group.
  • each of the amino groups represented by the symbol ##STR4## is a tertiary amino group.
  • R and R 1 represent either hydrogen or a lower alkyl group.
  • the term lower alkyl as used with regard to the basic amino groups includes groups having from 1 to 6 carbon atoms. Illustrative of such groups are both straight and branched chain alkyl groups, as for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isoamyl, n-pentyl and n-hexyl.
  • R and R 1 each represent lower alkyl, a preferred subgenus is formed.
  • Each R and R 1 of the basic amino function also represents a cycloalkyl group having from 3 to 6 carbon atoms. Such groups include the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals.
  • R and R 1 also represent an alkenyl group having from 3 to 6 carbon atoms.
  • the unsaturation present in this group must be in a position other than the 1 -position of the alkenyl group inasmuch as any unsaturation at this point is readily hydrolyzable.
  • Illustrative of such groups are the allyl, 3-butenyl and the 4-hexenyl radicals.
  • R and R 1 may also represent various saturated, monocyclic, heterocyclic radicals when taken in conjunction with the amino nitrogen atom to which they are attached.
  • Typical of such heterocyclic groups are the pyrrolidinyl, piperidino and morpholino radicals.
  • Compounds containing such groups are readily prepared and typify saturated, monocyclic, heterocyclic radicals which are generally useful in lieu of the dilower alkylamino groups present in the compounds of this invention.
  • the 2,7-bis-basic fluorenes, fluoren-9-ols and fluoren-9-ones described herein contain alkylene chains of various lengths ranging from 1 to a total of 4 carbon atoms as is indicated by the group --(CH 2 ) n -- in general formula (I) above.
  • the alkylene group may be either a straight or a branched chain and each alkylene group may be the same or different; preferably, however, both groups are the same.
  • Illustrative of such alkylene groups are methylene, ethylene, propylene, isopropylene and butylene.
  • sigma bond is intended to refer to the ordinary single bond linkage between two adjacent carbon atoms, resulting from the overlap of their corresponding orbitals.
  • A represents a sigma bond
  • the remainder of the side chain, ##STR5## is directly attached to the 2 and the 7-positions of the fluorene nucleus.
  • n is 1, the alkylene chain connecting the benzenoid nucleus with the basic amino group is methylene.
  • the maximum chain length of 6 carbon atoms is obtained where n is the integer 4 and A is either ##STR6##
  • 2,7-bis-basic fluorene compounds of the present invention represented by general formula (1) above, there can be mentioned: 2,7-bis(piperidinomethyl)fluorene, 2,7-bis(4-piperidinobutyl)fluorene, 2,7-bis(5-diethylaminopentyl)fluorene dihydrochloride, ⁇ , ⁇ '-bis(3-piperidinopropyl)-2,7-fluorenedimethanol, ⁇ , ⁇ '-bis(4-dimethylaminobutyl)-2,7-fluorenedimethanol, 2,7-bis(4-piperidino-1-buten-1-yl)fluorene, 2,7-bis [4-(N-methyl-N-cyclohexylamino)-1-buten-1-yl]fluorene, 2,7-bis(4-piperidinobutyryl)fluorene dioxime, 2,7-bis (5-morpholinovaleryl)fluoren
  • 2,7-bis-basic fluoren-9-ones represented by general formula (I) above are for example: 2,7-bis(piperidinomethyl)fluoren-9-one dihydrochloride, 2,7-bis(diallylaminomethyl)fluoren-9-one dihydrochloride, 2,7-bis[5-(4-methylpiperidino)pentyl]fluoren-9-one dihydrochloride, ⁇ , ⁇ '-bis(4-diethylaminobutyl)-9-oxofluoren-2,7-dimethanol, 2,7-bis(4-piperidino-1-buten-1-yl) fluoren-9-one, 2,7-bis[4-(N-methyl-N-cyclohexylamino)-1-buten-1-yl] fluoren-9-one, 2,7-bis(1-hydroxyimino-4-piperidinobutyl) fluoren-9-one, 2,7-bis[2-(hydroxyimino)-4
  • pharmaceutically acceptable acid addition salts is intended to apply to any organic or inorganic acid addition salts of the base compounds represented by formula (I) which are non-toxic.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids which form suitable salts are the mono, di and tricarboxylic acids, as for example, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxybenzoic, or the sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid.
  • Either the mono or the di-acid salts may be formed and such salts can be present in either a hydrated or a substantially anhydrous form.
  • the starting materials for the preparation of the compounds of the present invention are 2,7-bisbasic ketones having the general formula (II). These compounds are prepared via a Friedel-Crafts acylation of fluorene using an ⁇ -haloacyl halide to form the corresponding bis( ⁇ -haloacyl)fluorene. The subsequent amination of the bis( ⁇ -haloacyl)fluorene to form the corresponding 2,7-bis-ketones takes place under a variety of conditions using either ammonia, a primary or secondary amine. For example, the bis( ⁇ -haloacyl)fluorene can be heated with a large excess of amine, the excess amine serving as the reaction medium and hydrohalide acceptor.
  • the bis( ⁇ -haloacyl)fluorene may be heated with an amine in a suitable solvent such as toluene, dioxane or dimethylsulfoxide to effect condensation.
  • a suitable solvent such as toluene, dioxane or dimethylsulfoxide
  • the bis-basic oximes, (III) are prepared by the reaction of hydroxylamine with the 2,7-bis-basic ketones of formula (II). This reaction proceeds in from 2 to 48 hours at temperatures ranging from room temperature to about 100°C. Normally an excess of hydroxylamine is added in the form of its hydrochloride salt and the reaction conducted in a basic solvent such as pyridine or an alcohol containing sodium acetate or some other base which serves to release the hydroxylamine.
  • a basic solvent such as pyridine or an alcohol containing sodium acetate or some other base which serves to release the hydroxylamine.
  • the 2,7-bis-basic ⁇ -keto- ⁇ -hydroxyimino derivatives of fluorene (VI) are prepared from their corresponding bis-basic ketones (II) by nitrosating the active methylene groups in the ⁇ -position.
  • 2,7-bis-basic ketones (II) are dissolved in organic solvents such as methanol, ethanol, tetrahydrofuran and p-dioxane and the nitrosating agent generally added in small increments with stirring.
  • Useful nitrosating agents include the lower alkyl nitrites such as methyl, ethyl, n-butyl, amyl or isoamyl nitrite.
  • the reaction is generally conducted under anhydrous conditions in the presence of an excess of acid, such as gaseous hydrochloric acid, for a period of from 6 to 48 hours at or near room temperature.
  • the 2,7-bis-basic ⁇ , ⁇ -dioximes (VII) are prepared by the reaction of the corresponding 2,7-bis-basic ⁇ -keto- ⁇ -hydroxyimino derivatives (VI) with additional hydroxylamine hydrochloride.
  • the reaction is conducted in alcoholic solvents or aqueous-alcohol mixtures in the presence of a base such as sodium hydroxide or pyridine and generally proceeds in from about 1 to about 24 hours at a temperature ranging from about from room temperature to about 100°C.
  • the bis-basic- ⁇ , ⁇ -diketones (VIII) are prepared via the hydrolysis of either the corresponding bis-basic ⁇ -keto- ⁇ -hydroxyimino derivatives (VI) or the bis-basic ⁇ , ⁇ -dioximes (VII).
  • the hydrolysis reaction proceeds routinely in from 6 to 48 hours at tempertures ranging from about room temperature to about 100°C. in the presence of a strong acid. Suitable acids include hydrochloric or sulfuric acid present in concentrations of from about 5 to about 50%.
  • the bis-basic ⁇ , ⁇ -diketone salts so formed are generally water soluble and can be recovered in their free base form by neutralization of the reaction mixture with subsequent extraction of the reaction mixture with an organic solvent.
  • the bis-basic alkanols of the type illustrated in general formula (IV) are prepared from the corresponding bis-basic ketones (II) under conditions generally applicable for the reduction of ketones to alcohols.
  • Suitable reducing agents include metal hydride reducing agents such as lithium aluminum hydride with sodium borohydride having been found to be the reducing agent of choice. Two or more moles of sodium borohydride are generally used per mole of compound reduced, the additional borohydride serving to neutralize the salts of the bisbasic ketones to their free base forms.
  • the reaction is conducted in various organic solvents such as methanol, tetrahydrofuran or ether for periods ranging from a few minutes to about 24 hours. In general the reactants are mixed together at temperatures of 0°C.
  • reaction mixture is treated with water and the 2,7-bis-basic alkanols are isolated by conventional methods and purified by crystallization from an appropriate organic solvent.
  • Useful solvents include ether, benzene, chloroform, hexane or combinations thereof.
  • the 2,7-bis-basic vinylene derivatives (V) are prepared by the dehydration of the corresponding 2,7-bis-basic alkanols (IV) using a variety of dehydration methods as, for example, the pyrolytic elimination of the corresponding acetate and xanthate derivatives or, as is more generally employed, the acid catalyzed elimination of water.
  • the later method employs treating a solution of the 2,7-bis-basic alkanol with heat.
  • Suitable solvents include ethanol and ethylene glycol with dehydration temperatures ranging from about 70° to 120°C.
  • Preferred acid catalysts include concentrated hydrochloric or sulfuric acid. Reaction times vary from a few minutes to several hours.
  • the product may be obtained in the form of a salt directly from the reaction mixture, or, alternatively, as the free base by treatment of the reaction mixture with dilute alkali, followed by extraction of the free base into an organic solvent such as diethyl ether.
  • the 2,7-bis-basic alkanes (IX) are prepared from the corresponding 2,7-bis-basic ketones (II) via the general reaction conditions of the Wolff-Kishner reduction, utilizing hydrazine and a base catalyst in an organic solvent.
  • the desired product can be obtained by the direct reduction of the corresponding ketone, or the reduction may proceed in a stepwise fashion by the isolation of the hydrazone intermediate which is then subsequently reduced.
  • the 2,7-bis-basic ketones are dissolved in an organic solvent such as ethanol, diethylene glycol or p-xylene to which hydrazine and sodium or potassium hydroxide or alkoxide is added.
  • the reaction mixture is heated from about 140° to about 180°C for a period of from 12 to 48 hours to form the desired 2,7-bis-basic alkanes of fluorene.
  • Oxygen is bubbled through a pyridine solution of the 2,7-bis-basic fluorene or 2,7-bis-basic fluoren-9-ol derivative, containing a catalytic quantity of benzyltrimethylammonium hydroxide.
  • the reaction is conducted at room temperature for a period of from 1 to 24 hours.
  • Other strong bases such as alcoholic potassium hydroxide, sodium methoxide and potassium tert-butoxide, which are capable of forming a carbanion at the 9-position of the fluorene nucleus, can be used in place of the benzyltrimethylammonium hydroxide.
  • solvents as acetone, dimethyl sulfoxide, t-butyl alcohol and dimethylformamide may also be employed.
  • the 2,7-bis-basic fluoren-9-ols prepared by the chemical reduction of the corresponding base form of the 2,7-bis-basic fluorenone derivatives previously indicated in the reduction of the 2,7-bis-basic ketones of fluorene.
  • the 2,7-bis-basic methyl fluoren-9-ol derivatives represented by general formula (1), i.e., where A is a sigma bond and n is the integer 1, are prepared by the chemical reduction of the corresponding 2,7-bis-basic carboxamides of fluoren-9-one. These carboxamides are prepared by the reaction of 9-oxofluorene-2,7-dicarbonyl chloride with various amines including ammonia, primary and secondary amines.
  • the compounds of the present invention are antiviral agents. Preferably they are administered to an animal host to prevent or inhibit viral infections.
  • the term host refers to any viable biological material or intact animal including humans which is capable of inducing the formation of interferon and which serves as a support means for virus replication.
  • the host can be of animal or mammalian origin. Ilustratively such hosts include: birds, mice, rats, guinea pigs, gerbils, ferrets, dogs, cats, cows, horses and humans. Other viable biological materials, such as that used in the production of vaccines, may also act as a host.
  • tissue cultures prepared from organ tissues, such as mammalian kidney or lung tissue, as well as tissue cultures prepared from embryo tissue, such as obtained from amniotic cells and chick allatoic fluid have been found to be useful hosts.
  • the treatment of virus infections for purposes of the present invention encompasses both the prevention and the inhibition of characteristic disease symptoms in a mammalian host susceptible to invasion by a pathogenic virus.
  • mammalian virus infections which can be prevented or inhibited by the administration of the compounds of the present invention are infections caused by picornaviruses, such as encephalomyocarditis virus; myxoviruses, such as the influenza A 2 (Jap/305 virus; arboviruses, such as Semliki forest virus; the herpes group of viruses, including herpes simplex; and the poxviruses, as for example, vaccinia IHD.
  • picornaviruses such as encephalomyocarditis virus
  • myxoviruses such as the influenza A 2 (Jap/305 virus
  • arboviruses such as Semliki forest virus
  • herpes group of viruses including herpes simplex
  • poxviruses as for example, vaccinia IHD.
  • the compounds of the present invention when administered orally or subcutaneously to mice in varying doses either shortly prior or subsequent to a fatal inoculation of a neurotropic virus such as encephalomyocarditis virus, having a LD 50 of from 5 to 50, delay or prevent completely the onset of death.
  • Salts of these compounds of the present invention are generally administered in compositions containing a 0.15% aqueous hydroxyethylcellulose vehicle, whereas the free base compounds are generally administered in compositions containing a 10% aqueous surfactant vehicle in order to help solubilize the compound.
  • ten mice are used in each treated group with an additional 20 mice serving as a control group.
  • test virus is titrated in order to determine the potency or LD 50 for the particular virus pool used as a challenge.
  • the control animals are given a placebo containing the identical volume of vehicle without, of course, the active ingredient. Because of the lethal nature of the test system employed, the antiviral nature of the test compound is dramatically illustrated with a side by side comparison of the treated surviving animals and the untreated control group of animals.
  • Respiratory viruses such as influenza A 2 (Jap/305) virus, which are also lethal to the test animals employed, are adiministered via intranasal instillation. Animals infected in this manner have the active ingredients administered in the same manner as the test virus, and again a side by side comparison is made of the survivors of the animals treated with the untreated control animals.
  • a mouse fatally infected with encephalomyocarditis or influenza virus occasionally survives without further treatment. This may be the result of a prior, interferon-inducte infection in the mouse, or perhaps due to some genetic factor or other natural defense mechanism not presently understood. For this reason the control group selected is of sufficient size so as to statistically reduce to a negligible amount the influence of such a chance survivor upon the test results.
  • the vaccinia test virus is typical of the dermatotrophic type viruses which respond to treatment with compositions containing the compounds of the instant invention.
  • the vaccinia virus generally produces a non-fatal infection in mice, producing characteristic tail lesions when the virus is subcutaneously administered to the tail of the mouse.
  • the instant compounds are administered either orally or subcutaneously either prior to or subsequent to the vacinnia infection.
  • Tail lesions are subjectively scored on the eighth day following infection against untreated animals, which serve as a control group.
  • the compounds of the present invention have been found to be effective in varying degrees against one or all of these test viruses.
  • the compounds of the present invention may induce the formation of interferon in a viable host.
  • Interferon is a biological substance of unknown chemical structure, presumably proteinaceous in nature, which is produced by host cells in response to a viral infection.
  • the interferon so produced acts to induce the formation of a virus inhibiting substance, which inhibits in some yet unknown manner the intracellular replication of the virus without appearing to have any inactivation effect per se upon the virus.
  • a few of the viruses susceptible to interferon replication inhibition are described in Horsfall and Tamm, "Viral and Rickettsial Infections of Man", 4th Edition (1965), J.B. Lippincott Company, pp. 328-9.
  • the compounds of the present invention may be prophylactically administered in order to prevent the spread of contagious viral diseases, or they may be therapeutically administered to a host already infected intended for their curvative effect.
  • the administration be made within 0 to 96 hours prior to the infection of the host animal with a pathogenic virus.
  • the compounds of the present invention are administered for their curative effect, it is preferred that they be administered within about 1 or 2 days following infection of the host in order to obtain the maximum therapeutic effect.
  • the dosage administered will be dependent upon such parameters as the particular virus for which either treatment or prophylaxis is desired, the species of animal involved, its age, health, weight, the extent of infection, concurrent treatment, if any, frequency of treatment and the nature of the effect desired.
  • a daily dose of the active ingredients will generally range from about 0.1 mg to about 500 mg per kg of body weight.
  • dosage levels of the administered active ingredients for intravenous treatment range from about 0.1 mg to about 10 mg per kg of body weight; for intraperitoneal administration range from about 0.1 mg to about 50 mg per kg of body weight; for subcutaneous administration range from about 0.1 mg of about 250 mg per kg of body weight; for oral administration may be from about 0.1 mg to about 500 mg per kg of body weight; for intranasal instillation range from about 0.1 mg to about 10 mg per kg of body weight; and for aerosol inhalation therapy, the range is generally from about 0.1 mg to about 10 mg per kg of body weight.
  • novel compounds described herein can also be administered in various different dosage unit forms, i.e., oral compositions such as tablets, capsules, dragees, lozenges, elixirs, emulsions, clear liquid solutions and suspensions; parenteral compositions such as intramuscular, intravenous or intradermal preparations; and topical compositions, such as lotions, creams or ointments.
  • oral compositions such as tablets, capsules, dragees, lozenges, elixirs, emulsions, clear liquid solutions and suspensions
  • parenteral compositions such as intramuscular, intravenous or intradermal preparations
  • topical compositions such as lotions, creams or ointments.
  • the amount of active ingredient contained in each dosage unit form will, of course, vary widely according to the particular dosage unit employed, the animal host being treated, and the nature of the treatment, i.e., whether prophylactic or therapeutic in nature.
  • a particular dosage unit may contain from about 2.0 mg to
  • Suitable solid excipients include gelatin, lactose, starches, magnesium stearate and petrolatum.
  • Suitable liquid excipients include water and alcohols such as ethanol, benzyl alcohol and polyethylene alcohols either with or without the addition of a surfactant.
  • the preferred liquid excipients particularly for injectable preparations include water, saline solution, dextrose and glycol solutions, such as aqueous propylene glycol or an aqueous solution of polyethylene glycol.
  • Liquid preparations to be used as sterile injectable solutions will ordinarily contain from about 0.5% to about 25% by weight, and preferably from about 1% to about 10% by weight, of the active ingredient in solution.
  • various oils are utilized as carriers or excipients.
  • oils are mineral oils, glyceride oils such as lard oil, cod liver oil, peanut oil, sesame oil, corn oil and soybean oil.
  • a preferred method of administration for the compounds of the present invention is orally either in a solid dosage form such as a tablet or capsule, or in a liquid form such as an oral elixir, suspension, emulsion or syrup.
  • the active ingredient comprises from about 0.5% to about 10% by weight in an oral liquid composition.
  • the pharmaceutical carrier is generally aqueous in nature, as for example, aromatic water, a sugar-based syrup or a pharmaceutical mucilage.
  • suspending agents may be added as well as agents to control viscosity, as for example, magnesium aluminum silicate or carboxymethylcellulose. Buffers, preservatives, emulsifying agents and other excipients can also be added.
  • the proportion of active ingredient ranges from about 0.05% to about 20% by weight, and preferably from about 0.1% to about 10% by weight of the liquid composition.
  • such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of about 12 to about 17.
  • HLB hydrophile-lipophile balance
  • the quantity of surfactant in such formulations ranges from about 5% to about 15% by weight.
  • the surfactant can be a single surfactant having the above-identified HLB, or a mixture of two or more components having the desired HLB.
  • surfactants useful in parenteral formulations are the class of polyoxyethylene sorbitan fatty acid esters, as for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • concentration of active ingredient contained in these various parenteral dosage unit forms varies over a broad range and comprises anywhere from about 005% to about 20% by weight of the total formulation, the remaining component or components consisting of liquid pharmaceutical excipients previously mentioned.
  • the active ingredients of the present invention can also be admixed directly with animal feeds or incorporated into the drinking water of animals. For most purposes, an amount of active ingredient is used which provides from about 0.0001% to about 0.1% and preferably, from about 0.001% to about 0.02% by weight of the active ingredient based upon the total weight of feed intake.
  • the active ingredients can be admixed in animal feed concentrates suitable for use by farmers or livestock growers for incorporation in appropriate amounts with the final animal feeds. These concentrates ordinarily comprise from about 0.5% to about 95% by weight of the active ingredient compounded with a finely divided solid carrier or flour, such as wheat, corn, soybean or cottonseed flour.
  • nutrients and fillers may also be added such as ground cereal, charcoal, fuller's earth, oyster shells and finely divided attapulgite or bentonite.
  • the active ingredients of the present invention can be packaged in a suitable pressurized container together with an aqueous or volatile propellant for use as an aerosol.
  • a suitable discharge valve is fitted to an opening in the container from which the active ingredients may be conveniently dispensed in the form of a spray, liquid, ointment or foam. Additional adjuvants such as co-solvents, wetting agents and bactericides may be employed as necessary.
  • the propellant used is a liquidified gaseous compound, preferably a mixture of low molecular weight fluorinated hydrocarbons. These haloalkanes are preferred because of their compatibility with the active ingredients of the present invention, and because they are non-irritating when applied to skin surfaces.
  • Other useful propellants include ethylene oxide, carbon dioxide, propane and nitrogen gas.
  • the light yellow viscous oil which remains is dissolved in 400 ml of methanol, filtered, and 20 ml of 10% sodium hydroxide solution is added. To this mixture is added 4.0 g (0.1 mole) of sodium borohydride. The reaction is refluxed 2 hours under a blanket of nitrogen, cooled and excess sodium borohydride decomposed with 10% hydrochloric acid solution. The reaction mixture is made alkaline to phenolphthalein with 20% sodium hydroxide, and the mixture extracted 4 times with ether. The ether extracts are combined, washed 3 times with water, dried over anhydrous magnesium sulfate, filtered and the volatile components removed in vacuo.
  • a mixture of 6.15 g (0.016 mole) of 2,7--bis(piperidinomethyl)fluorene-9-ol, 12.1 ml of 10% hydrochloric acid, sufficient deionized water to bring the total volume to 150 ml, and 3.0 g of 10% palladium on charcoal catalyst is placed in a Paar hydrogenation apparatus and hydrogenated at room temperature for a period of 2 hours and 45 minutes.
  • the resulting mixture is filtered and sufficient 20% sodium hydroxide solution is added to render the mixture basic to phenolphthalein indicator.
  • the reaction mixture is extracted four times with chloroform, the extracts combined, washed twice with deionized water, treated with charcoal, filtered, and the major portion of the solvent removed at atmospheric pressure.
  • the antiviral activity of 2,7-bis[2-(hydroxyimino)4-piperidinobutyryl]fluorene dihydrochloride is illustrated by taking 30 mice each weighing approximately 10 to 12 gm and dividing them into two groups, a control group containing 20 animals and a test group of 10 animals. All of the animals are challenged with a fatal dose (4LD 50 ) of encephalomyocarditis virus. The test group of animals is treated both prophylactically and therapeutically using a parenteral composition which contains 2,7-bis[2-(hydroxyimino)-4-piperidinobutyryl]fluorene dihydrochloride as the active ingredient dissolved in a 0.15% aqueous hydroxyethylcellulose vehicle.
  • the composition contains the active ingredient in an amount such that each dose of 0.25 ml is equivalent to a dose level of 50 mg per kg.
  • the control group receives a subcutaneous placebo containing the same volume of vehicle without, of course, the active ingredient. Observations over a ten day period show a termination of all of the control animals within a period of from 4 to 5 days, with the treated group of animals surviving for a statistically greater period of time.
  • the active ingredient is uniformly mixed with the lactose and granulated by the addition of the starch paste.
  • the granules which form are dried at 120°F for 20 hours and forced through a No. 16 screen.
  • the granules are lubricated by the addition of the starch and calcium searate and compressed into tablets. Each tablet so prepared contains 100 mg of the active ingredient.
  • the finely powdered ingredients are mixed until uniformly dispersed and then filled into hard shelled gelatin capsules of the appropriate size.
  • soft gelatin capsules may be prepared in which the above composition can be granulated, slugged or directly compressed in a rotary die or plate mold in which the soft gelatin capsule is formed.
  • the above excipients may be omitted and the active ingredient dispensed as a powder directly into the soft gelatin capsule.
  • a 2% weight per volume syrup of 2,7-bis(diethylaminomethyl)fluoren-9-ol is prepared by the usual pharmaceutical techniques in accordance with the following formula:
  • the wool fat, white petrolatum and 200 gms of the light liquid petrolatum are liquified and held at 110°F.
  • the active ingredient is mixed with the remaining liquid petrolatum and passed through a colloid mill. After passing through the mill, the mixture is stirred into the melt, and the melt is permitted to cool with continued stirring until congealed.
  • composition for an emulsion which is parenterally injectable is as follows:
  • the parenteral composition is prepared by dissolving 0.64 g of sodium chloride in 100 ml of water suitable for injection.
  • the polyoxyethylene sorbitan monoolate is mixed with the active ingredient, and an amount of the previously prepared aqueous sodium chloride solution added which is sufficient to bring the total volume to 20 ml.
  • the resulting solution is shaken and autoclaved for 20 minutes at 110°C at 15 p.s.i.g. steam pressure.
  • the composition can be dispensed in a single ampule for use in multiple dosages or it can be dispensed as 10 or 20 individual ampules for use as a single dosage unit.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
US05/317,238 1972-12-21 1972-12-21 Fluorene compounds Expired - Lifetime US3983124A (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
US05/317,238 US3983124A (en) 1972-12-21 1972-12-21 Fluorene compounds
ZA738206A ZA738206B (en) 1972-12-21 1973-10-23 Fluorene compounds
AU61880/73A AU478050B2 (en) 1972-12-21 1973-10-26 Fluorene compounds
CA184,556A CA1017333A (en) 1972-12-21 1973-10-29 Fluorene compounds
IL43675A IL43675A (en) 1972-12-21 1973-11-21 2,7-bis-alkylaminoalkyl fluorene derivatives
DE2362663A DE2362663A1 (de) 1972-12-21 1973-12-17 Neue 2,7-bis-basische derivate von fluoren, 9-fluorenol und 9-fluorenon sowie diese enthaltende pharmazeutische zusammensetzung
GB5829073A GB1417267A (en) 1972-12-21 1973-12-17 Fluorene compounds
FR7345519A FR2211243B1 (enrdf_load_stackoverflow) 1972-12-21 1973-12-19
JP48141919A JPS4988849A (enrdf_load_stackoverflow) 1972-12-21 1973-12-20

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JP (1) JPS4988849A (enrdf_load_stackoverflow)
CA (1) CA1017333A (enrdf_load_stackoverflow)
DE (1) DE2362663A1 (enrdf_load_stackoverflow)
FR (1) FR2211243B1 (enrdf_load_stackoverflow)
GB (1) GB1417267A (enrdf_load_stackoverflow)
IL (1) IL43675A (enrdf_load_stackoverflow)
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3576865A (en) * 1968-10-11 1971-04-27 Richardson Merrell Inc Fluorenone-,fluorenol-,and fluorenebis-basic carboxamides
US3592819A (en) * 1968-12-30 1971-07-13 Richardson Merrell Inc Bis-basic ethers and thioethers of fluorenone,fluorenol and fluorene
BE764870A (fr) 1970-03-27 1971-08-16 Richardson Merrell Inc Cetones bis-basiques de fluorene et de fluorenone, ainsi que leur preparation
US3647860A (en) * 1969-01-09 1972-03-07 Richardson Merrell Inc Fluorene bis-basic esters

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3576865A (en) * 1968-10-11 1971-04-27 Richardson Merrell Inc Fluorenone-,fluorenol-,and fluorenebis-basic carboxamides
US3592819A (en) * 1968-12-30 1971-07-13 Richardson Merrell Inc Bis-basic ethers and thioethers of fluorenone,fluorenol and fluorene
US3647860A (en) * 1969-01-09 1972-03-07 Richardson Merrell Inc Fluorene bis-basic esters
BE764870A (fr) 1970-03-27 1971-08-16 Richardson Merrell Inc Cetones bis-basiques de fluorene et de fluorenone, ainsi que leur preparation

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FR2211243B1 (enrdf_load_stackoverflow) 1976-12-31
IL43675A (en) 1976-07-30
GB1417267A (en) 1975-12-10
DE2362663A1 (de) 1974-06-27
FR2211243A1 (enrdf_load_stackoverflow) 1974-07-19
IL43675A0 (en) 1974-03-14
ZA738206B (en) 1974-09-25
CA1017333A (en) 1977-09-13
JPS4988849A (enrdf_load_stackoverflow) 1974-08-24
AU6188073A (en) 1975-05-01

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